The preparation of Entacapone, formula (1), has been reported in GB 2,200,109 and U.S. Pat. No. 4,963,590 from two critical intermediates viz; 3,4-dihydroxy-5-nitrobenzadehyde (formula (5)) and N,N-diethylamino-cyanoacetamide (formula (3)). The compound of formula 5 was condensed with compound 3 in the presence of piperidine acetate and dry ethanol as a solvent to provide Entacapone. The 3,4-dihydroxy-5-nitrobenzaldehyde was prepared from 3-methoxy-4-hydroxy-5-nitrobenzaldehyde (6) using acetic acid and hydrobromic acid, as illustrated in Scheme 1.

The above patent described the preparation of Entacapone (1) without describing the stereochemistry or the polymorphism.
Subsequently it was described in the U.S. Pat. No. 5,135,950 described preparing the E-isomer and polymorphism-A from the mixture obtained from the reaction reported in the GB Patent No. 2,200,109.
The main disadvantage of this method, according to our findings, is that the reaction times are very long, ranging about 84-100 hours, and the reaction never goes to completion.
Furthermore, the preparation of compound 5 from 3-hydroxy-4-methoxy-5-nitrobenzadehyde 6 as described in Scheme 1 has to be purified repeatedly and the yield compound 5 is only about 55%. Consequently, the yield of the final product is also very low.
The critical raw material 3,4-dihydroxy-5-nitrobenzaldehyde (5), a catechol derivative, changes color from light yellow to a dark color upon storage at room temperature in a short period of time. The yield and quality (purity) of the Entacapone product varies between batches and there is no consistency in yield and quality. Hence storing of this compound required special conditions, such as below 15° C. in the absence of light.
In addition, it was known in the literature that catechol derivatives are known to undergo aerial oxidation and give quinone derivatives. Such oxidations contribute to the color changes during storage.
Accordingly, it is of paramount important to find a stable penultimate stage intermediate that is stable at room temperature for longer durations and can be stored and used required. The overall yield of the Entacapone final product by the present route (described above) is about 58%.